Mycobacterium tuberculosis (Mtb) is the causative agent of tuberculosis. Tuberculosis is primarily a disease of the lungs and is characterized by chronic coughing, blood-tinged sputum, fever, night sweats, and a loss of appetite. The current World Health Organization (WHO) approved therapy for treating TB is a four-drug combination of isoniazid, rifampicin, pyrazinamide and either ethambutol or streptomycin. This 6-month regimen for treating TB is known as directly-observed therapy short course (DOTS). New and improved drug therapies are needed that will decrease the treatment period and combat both the increasing rate of infection and the emergence of multi-drug resistant TB (MDR-TB) and extensively drug resistant TB (XDR-TB).
Two mechanisms are known for the biosynthetic production of isoprenoid units: the mevalonate pathway found in mammals and plants, and the nonmevalonate pathway found in most bacteria. There are no human homologues for the enzymes of the nonmevalonate pathway and each enzymatic reaction is vital to the survival of bacteria. These enzymes are thus prospective targets for therapeutic intervention of M. tuberculosis. 1-Deoxy-D-xylulose-5-phosphate reducto-isomerase (Dxr), an enzyme in the non-mevalonate pathway, is essential for the growth of Mtb. Dxr is responsible for the conversion of 1-deoxy-D-xylulose-5-phosphate (Dxp) to 2-C-methyl-D-erythritol-4-phosphate (MEP) and is the first committed step in the nonmevalonate pathway. Current anti-TB drugs do not target the nonmevalonate pathway, so Dxr inhibition would be a new mechanism of action. Accordingly, Dxr provides a convenient target for developing drugs against Mtb.